Cancer (and other hyperproliferative diseases) is characterized by uncontrolled cell proliferation. This loss of the normal control of cell proliferation often appears as the result of genetic damage to cell pathways that control progress through the cell cycle. Such damage includes abnormal DNA methylation in malignant cells, in particular methylation of tumor suppressor genes. (Robertson, K. D., et al., Oncogene, 2001, 20, 3139-3155; Jones P. A., et al., Nat. Rev. Genet., 2002, 3, 415-428).
DNA methylation is mediated through DNA methyltransferases (DNMTs). DNMT1, 3a and 3b activity in tumors is essential for perpetuating gene silencing in growth-regulating genes. Elevated levels of DNA methyltransferases, in tumors contribute to tumorigenesis by improper de novo methylation and silencing of tumor suppressor genes (Linhart H. G., et al., Genes Dev., 2007, 21, 3110-3122). For example, DNMT3b protein overexpression was reported as an independent prognostic factor for predicting cancer survival in diffused large B-cell lymphoma patients (Amara, K., et al., Cancer Sci., 2010, 101, 1722-1730). In another example, depletion of DNMT3a was shown to suppress cell proliferation and to restore PTEN in hepatocellular carcinoma cells (Zhao Z., et al., J. of Biomed. & Biotech., Volume 2010, Article ID 737535, 10 pages).
It has been proven that DNA hypomethylating agents, such as decitabine, are useful for the treatment of cancers. Inhibition of DNMT function would lead to a DNA hypomethylating stage. Thus, small molecule inhibitors of DNMTs should be useful in the treatment of diseases involving uncontrolled cell proliferation, and in particular of cancers (Sippl, W., et al., Methods and Principles in Medicinal Chemistry Volume 42, Epigenetic Targets in Drug Discovery, Chapter 8, 2009, 163-183).
One approach to design DNMT inhibitors is to mimic the co-factor (L)-S-adenosyl-L-methionine (SAM) or its metabolite (L)-S-adenosyl-L-homocysteine (SAH). Such an approach has been described in various publications (Wehhab A., et al., US2008/0132525; Isakovic L., et al., Bioorg. Med. Chem. Lett., 2009, 19, 2742-2746; Saavedra O. M., Bioorg. Med. Chem. Lett., 2009, 19, 2747-2751). The present invention is focusing on SAM or SAH mimics. These mimics contain a functional group that is suitable to interact with the DNA binding region, in particular the cytosine binding pocket. Similarly, novel functional groups that can serve as adenosine mimics are described. Such small molecules can bind to DNMTs in a covalent or non-covalent manner, and in turn inhibits the enzymes. Such small molecules should be useful for treating diseases involving uncontrolled cell proliferation, in particular for cancer.
US 2008/0132525 and WO 2006/078752 describe inhibitors of DNA methyltransferase. CA 2030875 describes methods and probes for detecting nucleoside transporter and method for producing the probes. U.S. Pat. No. 7,560,467 describes indazolo-tetrahydropyrimidine-carboxamide derivative kinase inhibitors. US 2002/0068734, U.S. Pat. No. 6,472,391 and U.S. Pat. No. 6,750,218 describe nitrogen-containing heterocyclic compounds. U.S. Pat. No. 6,169,088 and U.S. Pat. No. 6,207,667 describe 1,3 diazines with platelet-derived growth factor receptor inhibitory activity.